1. Technical Field
The field of this invention is the modulation of leukocyte homing to provide therapies for inflammation and other pathogenic conditions associated with leukocyte infiltration into tissue.
2. Background
The bloodstream is the pathway for numerous cells which migrate throughout the body, monitoring conditions. Cells of the lymphoid and myelomonocytic lineages act to identify foreign substances, such as pathogens, aberrant cells, and some compounds, and remove them from the system. These cells have available a large variety of mechanisms for protecting the host from the foreign substance. Many of these mechanisms are highly destructive and result in cytotoxicity of native tissue, inflammation, degradation, and the like. Mechanisms may involve the production of superoxide, secretion of various degradative compounds, such as performs, endocytosis, etc.
While in many situations these protective mechanisms are salutary, in many other situations, they are found to have detrimental effects, involving inflammatory lesions, such as myocarditis, inflammatory bowel disease, psoriasis, allergic contact dermatitis, lichen planus, lymphoid hyperplasia in the skin, inflamed synovia, reperfusion injury, etc. There is, therefore, an interest in being able to modulate the effects of these various monitoring cells.
In recent years, it has been shown that the migrating cells have specific surface membrane proteins associated with their homing or being directed to a particular site. Specialized venules including the high endothelial venules, serve as beacons for these cells, expressing proteins referred to as endothelial leukocyte adhesion molecules and addressing, which bind to the xe2x80x9choming receptorsxe2x80x9d or adhesion molecule surface membrane proteins of the migrating cells. After binding to the venules, the cells migrate by diapedesis, by mechanisms unknown, to the site of inflammation or injury. Therefore, by interfering with the binding between the endothelial cell and the leukocyte adhesion element, one may hope to reduce the infiltration of migrating cells into the inflamed site to prevent further aggravation of the site.
Relevant Literature
References associated with the characteristics of HECA-452 include Picker et al., J. Immunol. (1990) 145:3247-3255; Raine et al., Clin. Immunol. Immunopathol. (1990) 57:173-187; Jalkanen et al., J. Invest. Dermatol. (1990) 94:786-792; Picker et al., Am. J. Pathol. (1990) 136:1053-1068; VanDinther-Janssen et al., J. Rheumatol. 17:11-17; Jalkanen et al., Int. J. Cancer (1989) 44:777-782; Facchetti et al., Immunol. Lett. (1989) 20:277-281; Seldenrijk et al., Gut (1989) 30:46-491; Kabl et al., J. Clin. Endocrinol. Metab. (1989) 62:744-751; van der Valk et al., Am. J. Surg. Pathol. (1989) 13:97-106; Duijvestijn et al., Am. J. Pathol. (1988) 130:147-155; and Graber et al., J. Immunol. (1990) 145:819-830.
Lowe et al., Cell (1990) 63:475-484; Phillips et al., Science (1990) 250:1130-1132; Walz et al., Science (1990) 250:1132-1135; and Goelz et al., Cell (1990) 63:1349-1356, report a neutrophil carbohydrate ligand for ELAM-1 as NeuAcxcex12,3-galxcex21-4[Fucxcex11,3]GlcNac, the sialylated-Lewis X antigen, or sialylated lacto-N-fucopentaose III (sLNFIII).